HMG-CoA reductase or 3-hydroxy-3-methyl-glutaryl-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. Competitive inhibitors of HMG-CoA reductase increase the expression of low density lipoprotein (LDL) receptors in the liver, which in turn increases the catabolism of plasma LDL and decreases the plasma concentration of cholesterol, an important determinant of atherosclerosis. Therefore, HMG-CoA reductase has therefore been a target for pharmaceutical intervention, resulting in a group of widely available cholesterol-lowering drugs known collectively as the statins. These drugs include for example of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, mevastatin and rosuvastatin. However, despite increasing use of statins, even in optimal doses to achieve target LDL-cholesterol reduction, considerable residual risk remains. Such risk resides in elevated levels of triglycerides (TG), and subnormal levels of artheroprotective high-density lipoprotein cholesterol (HDL-cholesterol) [Lai et al. Lipids in Health and Disease, 2014, 13:1].
The metabolic cofactor coenzyme A (CoA) is an acyl group carrier involved in the oxidative catabolism of fatty acids as well as in transferring fatty acids from the cytoplasm to mitochondria. CoA is essential for over 100 metabolic reactions, and it has been estimated that CoA is an obligatory cofactor for 4% of known enzymatic reactions. Eukaryotic cells are believed to obtain this essential cofactor via an intracellular de novo biosynthetic route. This canonical pathway starts with the uptake of extracellular vitamin B5, which is converted via five conserved enzymatic reactions into intracellular Coenzyme A. These enzymes are, in order, pantothenate kinase, phosphopantothenoyl cysteine synthetase, phospho-N-pantothenoylcysteine decarboxylase, phosphopantetheine adenylyltransferase and dephospho-CoA kinase.
Administering patients with moderate dyslipidemia with CoA was shown to effectively reduce plasma triglyceride levels [Chen et al., J Clin Enocrinol Metab, 2013, 98: E275-E278]. It has been described that combinations of statins and Coenzyme A in patients with hypercholesterolemia and hypertriglyceridemia, improved triglyceride levels and other lipoprotein parameters to a greater extent than statin alone [Lai et al. Lipids in Health and Disease, 2014, 13:1]. Similar combinations have also been shown effective in reducing plasma lipid levels rabbits and rats [Na et al., Academic Journal of Second Military Medical University, 2004, 25:255-257]. However, due to its complex chemical structure Coenzyme A is not readily available in industrial amounts through chemical synthesis. Coenzyme A from microbial sources, can be obtained, however yields are relatively low and isolation complex [Nishimura et al., Appl Microbiol. 1974, 28:117-23; Shimizu et al., Appl Environ Microbiol. 1984, 48:1118-22], therefore coenzyme A is not widely available in pure form.